Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
  • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
  • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/30—Preparation of optical isomers
  • C07C227/32—Preparation of optical isomers by stereospecific synthesis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the invention described herein relates to derivatives of (R) and (S)-carnitine, and particularly nitriloxy derivatives which are useful as intermediate synthesis products and as therapeutic agents.
• Organ ischaemia is caused by an imbalance between the oxygen requirements of the tissue and oxygen availability from the bloodstream. In the particular case of cardiac ischaemia, this If manifests with typical symptoms, known as angina pectoris. The causes are multiple and, among them, we should mention the reduced ability of the coronary circulation to supply oxygen, owing, for example, to the presence of atheromatous plaques.
• myocardial infarction One possible consequence of the ischaemia is myocardial infarction.
• Myocardial ischaemia may also be asymptomatic and detectable only by means of clinical and instrumental examinations.
• the therapy currently available is based mainly on the administration of coronary dilating drugs, which, on account of the specific needs of symptomatological treatment, have to have as rapid an action as possible.
• Calcium antagonists, ⁇ -adrenergic antagonists and antiaggregant agents should also be mentioned.
• Amyl nitrite is used by inhalation in cases of angina attack. Nitroglycerine and organic nitrates of higher molecular weight are also used for the prevention of such attacks. Nitroderivatives are associated with a series of important side effects. The most common of these is headache, which may even be very severe. More serious is the fact that these drugs give rise to tolerance and their withdrawal causes a rebound effect. Nitroglycerine is also administered using transdermal release systems, which, however well designed they may be, present problems in their own right, such as those relating to permanence at the application site, controlled delivery of the drug and patient compliance.
• Calcium antagonists present the problem of excessive vasodilatation, with consequent dizziness, hypotension, headache, and nausea, and it is by no means easy to establish the appropriate therapeutic regimen.
• ⁇ -antagonists have effects on cardiac haemodynamics.
• Patent application WO98/56759 describes pentaerythrite derivatives of general formula (O 2 NOCH 2 ) m C(CH 2 OH) n (CH 2 COR 1 ) o (COR 1 ) p .
• the multiple meanings of R 1 include nitriloxy derivatives of carnitine, in particular nitriloxy-carnitine chloride, its inner salt and ester with (1-alkoxy-carbonylmethyl-2-trialkylammonium)ethanol.
• Nitriloxy-carnitine is also envisaged, provided on mixtures containing equimolar amounts of (R) and (S) isomers.
• the anti-angina activity of these compounds is mentioned in the description.
• Nitriloxy-carnitine is also prepared as an intermediate.
• the examples of the compounds are provided on the racemic mixtures.
• the only example of a preparation, example 17, which uses L-carnitine, envisages reaction with the chloride of 3-nitriloxy-2,2-bis(nitriloxymethyl)propionic acid.
• L-carnitine in the treatment of heart failure is known (U.S. Pat. No. 3,830,931).
• Alkanoyl derivatives of L-carnitine are known for different uses in human or animal therapy.
• Nitriloxy derivatives of (R) and (S)-carnitine are also useful intermediates for synthesis for the production of chiral 3-4 carbon atom synthons having the (R) or (S) configuration, such as for example 3-hydroxy- ⁇ -butyrolactone, 1,2,4-butantriole, 3-hydroxytetrahydrofurane, 3-hydroxypyrrolidine, 2,3-dihydroxypropylamine, to be used in the industrial synthesis of enantiomerically pure drugs.
• (R) and (S)-carnitine are not actually available at low cost, therefore a process convenient and applicable on a large scale, allowing the stereospecific conversion of (S)-carnitine into (R)-carnitine or vice-versa will be economically advantageous and useful.
• Y is an OR or NR 1 R 2 group with
• R equal to hydrogen, C 1 -C 10 alkyl or alkyl substituted with C 6 -C 10 aryl, said aryl optionally carrying one or more C 1 -C 4 alkyls;
• R 1 and R 2 which may be the same or different, are hydrogen, C 1 -C 10 alkyl or alkyl substituted with C 6 -C 10 aryl, said aryl optionally carrying one or more C 1 -C 4 alkyls; or, taken together, form a 5-7 atom heterocyclic ring with the nitrogen atom;
• Y is the residue of an esterified polyalcohol with at least one nitric acid equivalent
• X ⁇ is the anion of a pharmaceutically acceptable organic or inorganic acid
• the formula (I) product may exist in the form of an inner salt, i.e. with structure (II)
• C 1 -C 10 alkyls are methyl, ethyl propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl and all their possible isomers.
• substituted alkyls examples include benzyl and phenylethyl.
• substituted aryls examples include tolyl, xylyl and its isomers.
• polyalcohols examples include glyceryl mono- or dinitrate, isosorbide mononitrate, erythrityl di- o trinitrate, pentaerythrityl mono-, di- or trinitrate.
• Examples of anions of organic or inorganic acids are NO 3 ⁇ , Cl ⁇ , Br ⁇ , I ⁇ , HSO 4 ⁇ , (SO 4 2 ⁇ ) 0.5 , H 2 PO 4 ⁇ , (HPO 4 2 ⁇ ) 0.5 , (PO 4 3 ⁇ ) 0.33 , a residue of a hydroxy acid, a residue of a bicarboxylic acid, OSO 2 Z ⁇ , OCOZ ⁇ or OCOH ⁇ with Z equal to C 1 -C 10 alkyl, substituted alkyl, such as, for example, trihalomethyl or benzyl, aryl, such as, for example, phenyl, tolyl, halophenyl or alkoxyphenyl.
• halogen is fluorine, chlorine, bromine and iodine.
• Preferred examples of anions of organic and inorganic acids are those derived from pharmaceutically acceptable acids, among which, in addition to those exemplified above, we would mention particularly mandelate, orotate, acid aspartate, acid citrate, fumarate and acid fumarate, maleate and acid maleate, mucate, malate and acid malate, glucose phosphate, tartrate and acid tartrate, succinate, acid succinate, oxalate.
• heterocyclic ring with 5-7 nitrogen atoms examples include tetrahydropyrrhol, piperidine, piperazine, morpholine, alkyl-morpholine and azepine.
• a further subject of the invention described herein is the process for the preparation of formula (I) or (II) compounds, using procedures which are in themselves known, starting from formula (III) compounds with known nitrating agents, such as, for example, concentrated nitric acid, a nitric acid/sulphuric acid mixture, a nitric acid/acetic anhydride mixture, etc., when T is a hydroxy group or when T is a good leaving group; or by means of treatment with alkaline nitrates, earth-alkaline nitrates, silver nitrate, ammonium nitrate or tetra-alkylammonium nitrate, when T is a good leaving group, such as, for example, an OSO 2 Z group, where Z is as defined above.
• known nitrating agents such as, for example, concentrated nitric acid, a nitric acid/sulphuric acid mixture, a nitric acid/acetic anhydride mixture, etc.
• T is a hydroxy group or T is a leaving group
• X 1 ⁇ equal to or different from X ⁇ , being included in the meanings illustrated above.
• the X ⁇ group as required and using techniques in themselves known, such as the use of ion-exchange resins or by means of electrodialysis, can be varied in the context of the possibilities listed above, subsequent to treatment with the nitrating system.
• Formula (III) products are optically active and, according to the nitrating system used, formula (I) products can be obtained, with the same absolute configuration as the formula (III) products or with the opposite absolute configuration, and, to be precise, retention of absolute configuration occurs when the nitrating agent used in the course of the reaction does not involve the formation of a bond with the asymmetric carbon atom, while inversion of configuration is observed when using nitrating agents whose mechanism of action involves an S N 2 nucleophilic substitution reaction with substitution of the T group.
• a further subject of the invention described herein is the use of formula (I) compounds, and particularly of derivatives with Y equal to an OH group and X ⁇ equal to NO 3 ⁇ , Cl ⁇ , OSO 2 Z ⁇ or OCOZ ⁇ with Z equal to C 1 -C 10 alkyl, or of the formula (II) compound, preferably in the optically active form of absolute configuration (R) and in the case of enantiomerically enriched mixtures, said mixtures preferably comprising an amount of the enantiomer (R) higher than 95%, as pharmaceutically active anti-angina ingredients in solid and liquid pharmaceutical compositions for oral administration, parenteral administration, transdermal use or sublingual use in the treatment of ischaemic heart disease.
• compositions include a pharmaceutically effective dose of the active ingredient, optionally in mixtures with pharmaceutically acceptable vehicles or excipients.
• the invention described herein also relates to a therapeutic method for the treatment of angina pectoris and of various ischaemic forms, comprising the administration of said compositions in amounts corresponding to 1-200 mg of active ingredient per day orally, of 0.1-10 mg of active ingredient per day parenterally, or of equivalent effective daily doses of active ingredient sublingually or transdermally, preferably 0.1-200 mg of active ingredient per day sublingually, and 0.1-100 mg of active ingredient per day transdermally.
• a further aspect of the invention described herein is a process for producing (R)-carnitine on an industrial scale starting from the corresponding (S) enantiomorph, which is a raw material available in large amounts and at low cost, in that it is easily obtainable as a by-product of industrial processes of resolution of the racemic mixture of (R,S)-carnitine or (R,S)-carnitinamide with optically active acids such as tartaric acid, tartaric dibenzoyl acid, camphoric acid or camphorsulphonic acid, by means of the formation of derivatives of general formula (I) or (II).
• the process according to the present invention which uses formula (I) derivatives, and preferably the one with Y ⁇ OH and X ⁇ ⁇ NO 3 ⁇ , of absolute configuration (S), or the formula (II) compound of absolute configuration (S), easily obtainable starting from (S)-carnitine by treatment with acid nitrating mixtures, makes it possible to obtain (R)-carnitine, in a very simple manner, with a lower number of steps, a high yield and high stereospecificity, by treatment with inorganic and organic bases of the aforementioned formula (I) or (II) products in water or in mixtures of water and organic solvent mixable in water, operating at a pH value ranging from 7 to 10, and preferably at a pH value ranging from 7.5 to 9.5 and even more preferably from 8 to 9 and at a temperature of 50-100° C.
• the preferred bases are bicarbonates of alkaline or alkaline-earth metals and potassium phthalimide.
• a further aspect of the invention described herein is the process for preparing (R)-carnitine from (S)-carnitine or vice versa through the use of the formula (IV) intermediate enantiomerically enriched of absolute configuration (R) and (S), respectively, prepared in any way and preferably starting from a formula (I) derivative with Y ⁇ OR or NR 1 R 2 with R ⁇ H, C 1 -C 10 alkyl, or substituted alkyl and where R 1 R 2 , equal or different from one another, are alkyl, hydrogen R 1 R 2 and X ⁇ ⁇ NO 3 ⁇ by treatment with organic or inorganic bases in water or in mixtures of water and organic solvent mixable with water.
• the preparation is done as in example 1, but, at the end of the reaction, most of the excess HNO 3 and acetic acid is distilled off at reduced pressure (10 mm Hg).
• nitric acid 150 g is dehydrated by addition of Ac 2 O at 5° C. (297.7 g). Again at 5° C., (S)-carnitine inner salt (50 g) and more acetic anhydride (31.5 g) are added in sequence. On completing the additions, the reaction is left to proceed at room temperature for 17 h and the excess nitric acid is then distilled at reduced pressure (20 mm Hg). The residue is precipitated by addition of EtOAc (1.2 l) obtaining (S)-3-nitriloxy-carnitine nitrate (66.8 g; yield 80%).
• 65% nitric acid (150 g) is dehydrated by addition of Ac 2 O at 5° C. (300 g; 3.1 moles). Again at 5° C., (S)-carnitine inner salt (100 g; 0.62 moles) and more acetic anhydride (63 g) are added in sequence. The cooling is then removed and, after 18 h at room temperature, the residue is precipitated with ethyl acetate (2.4 l) to obtain (S)-3-nitriloxy-carnitine nitrate (134 g; yield 80.5%).

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• 1999
  • 1999-08-05 IT IT1999RM000508A patent/IT1306184B1/it active
• 2000
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  • 2000-07-31 WO PCT/IT2000/000325 patent/WO2001010819A1/en active IP Right Grant
  • 2000-07-31 DK DK00951861T patent/DK1224161T3/da active
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